Aging has been shown to be under genetic control in model organisms. One of the genes that determines longevity in yeast and C. elegans (roundworms) is SIR2. The greater the activity of SIR2, the longer the life span in these organisms. The biochemical activity of Sir2 protein is that of an NAD-dependent histone deacetylase. A major challenge now is to determine how this activity might determine life span and whether the longevity dictated by SIR2 is subject to physiological regulation. One established physiological regimen that has been shown to extend life span is calorie restriction (CR). Limiting the calories in the diet extends the life spans of rodents, fruit flies, worms, and yeast. The mechanism by which CR extends life span is not clear. In yeast the extension induced by CR requires SIR2, implying that Sir2 protein and NAD are involved in the mechanism. In this proposal we will establish a petri plate-based replica of CR in worms and test the possible involvement of the sir-2 genes of this animal in the response to CR. Further, we will probe by genetic and molecular approaches how the sir-2.1 gene of C. elegans extends life span in this animal by regulating the known pathway of insulin signaling in worms. These studies ought to pinpoint the roles that the four sir genes play in the determination of life span in C. elegans. They also may shed light on a molecular mechanism of CR in an animal. These findings may have direct relevance to aging and the extension of life span by CR in mammals.